Asthma is a common chronic inflammatory disorder of the airways. The number of sufferers has increased dramatically over recent decades and the World Health Organisation estimates that in the region of 300 million people worldwide suffer from asthma. Allergic asthma is characterised by uncontrollable airways hyperresponsiveness (AHR) induced by a variety of provocative stimuli and is associated with type-2 inflammatory infiltrates into the lungs.
Inflammatory bowel disease (IBD) is a chronic inflammation affecting the mucosal layer of the colon (also known as the large intestine), which includes two disease conditions: ulcerative colitis (UC) and Crohn's disease (CD). Conventional therapies for treatment of IBD involve either antibiotics or steroid-derived drugs or anti-TNF-α agents; however, these are not currently successful in inducing or maintaining clinical remission in patients (Hanauer et al., 2008). UC is thought to be a Th2-mediated disease, with a representative mouse model showing involvement of type 2 cytokines in the development of gut inflammation (Heller et al., 2002)
The interleukin-17B receptor, variously known as IL-25R, IL-17BR, IL-17RB or IL-17RH1 was first identified in an expressed sequence tag database by its homology to the IL-17A receptor (IL-17RA) (Tian et al., 2000). IL-17BR has subsequently been shown to bind both IL-17B and IL-25 (Lee et al., 2001; Shi et al., 2000; Tian et al., 2000). IL-25 binds to IL-17BR with a stronger affinity (1.4 nM) than IL-17B (7.6 nM).
IL-25, a member of the IL-17 cytokine family (IL-17A, IL-17B, IL-17C, IL-17D and IL-17F—associated with type-1 inflammation), differs strikingly from other IL-17 family members in that its production induces type-2 cytokine expression associated with splenomegaly, elevated serum levels of IgG1 and IgE and pathological changes in the lungs and digestive tract including eosinophilic infiltrates, increased mucus secretion and epithelial cell hyperplasia (Fort et al., 2001; Lee et al., 2001; Moseley et al., 2003; Pan et al., 2001). Genetic ablation of IL-25 or the use of blocking anti-IL-25 antibodies have clearly demonstrated the importance of IL-25 in protecting from helminth infection (Fallon et al., 2006; Owyang et al., 2006), but also its critical role in regulating responses characteristic of asthma (Ballantyne et al., 2007). It appears that IL-25 stimulates these responses through its ability to induce the release of type-2 cytokines, such as IL-13, initially from innate non-B/non-T (NBNT) cells (Fallon et al., 2006; Fort et al., 2001) and subsequently from the adaptive T cell response (Angkasekwinai et al., 2007; Wang et al., 2007).
il17br message has been identified in libraries from lung, brain, pancreas, kidney, thyroid and eosinophils (Lee et al., 2001; Shi et al., 2000). Expression in lung smooth muscle cells seems to be immunologically regulated (Lajoie-Kadoch et al., 2006).
Consistent with a role in asthma, IL-25 mRNA or protein has been detected from a number of cell types found in the lung including alveolar macrophages, mast cells, eosinophils, and basophils (Wang et al., 2007). More recently, IL-25 production by allergen-stimulated human and mouse lung epithelial cells has supported a potential role for IL-25 modulating allergic pulmonary responses (Angkasekwinai et al., 2007). In addition, IL-25 has been reported to induce inflammatory cytokine and chemokine production from lung fibroblasts, and components of extra-cellular matrix from airway smooth muscle cells. Furthermore, recent studies have indicated that transcripts for IL-25 and IL-17BR are significantly upregulated in biopsy tissue from asthmatic patients, associated with eosinophilic infiltration (Wang et al., 2007). Treatment of OVA sensitised mice with a blocking monoclonal antibody directed against IL-25 results in a decreased AHR and lower IL-13 concentrations in the bronchoalveolar lavage in response to OVA challenge and methacholine administration.
Recently, Rickel et al. (J Immunol 181, 4299-4310 (2008)) used a blocking monoclonal antibody to human IL-17RA to prevent IL-25 activity in a primary human cell-based assay. This showed that IL-25 activity requires both IL-17BR and IL-17RA. However, it has also been reported that IL-17A and IL-17F signal through a heteromeric complex containing IL-17RA and IL-17RC.
Rickel et al. also describe an antibody reactive with mouse IL-17BR which blocks IL-25-induced lung inflammation in a mouse model of allergic asthma. To date, no antibodies reactive with human IL-17BR have been reported.
Consistent with a role in IBD, IL-25 production has been observed in an experimental model of chronic colitis in mouse, in association with a switch from a Th1 to a Th2 type response (Fichtner-Feigl et al., 2008) and high mRNA expression of IL-25 was found throughout the gastrointestinal tract in mice (Fort et al., 2001). Moreover the IL-25 gene is located within a Crohn's disease susceptibility region on chromosome 14 in humans, although its potential association with the disease remains to be investigated (Buning et al., 2003).